PROJECT SUMMARY/ABSTRACT Research: Veterans of the U.S. military die by suicide at a rate of two to six times that of their civilian counterparts. Suicidal ideation (SI) and suicide attempts (SA), cardinal precursors to death by suicide, occur at significantly greater frequency than death and cause immense individual and societal burden, yet relatively little is known about their pathophysiology. This is especially so in posttraumatic stress disorder (PTSD), a signature injury of the wars in Iraq and Afghanistan. High rates of comorbidity and inflated prevalence of both suicidality and PTSD in Veterans, highlights the urgency of advancing understanding of the shared and distinguishing neural mechanisms between these. Evidence of trauma- and stress-related synaptic loss and large-scale alterations in intrinsic connectivity networks in brain regions implicated in mood, cognition, and behavior exists in both SI/SA and PTSD literature. However, a major obstacle in field is the scarcity of neurobiologically-based studies of SI/SA in PTSD cohorts. Preliminary data supports the notion that the location and pattern of synaptic alterations may interact with individual and environmental characteristics to affect clinical presentation and symptom severity. Specifically, Veterans with PTSD endorsing SI appear to have a neural signature of synaptic alterations distinct from PTSD symptom severity, depression, and age. Extending this work, state-of-the-art multimodal neuroimaging and behavioral assessment sessions will be conducted in 96 Veterans across 3 study groups (n=32/group): PTSD only; PTSD+SI; PTSD+SA. Robust, complimentary evidence of a unique pattern and location of synaptic alterations will be demonstrated using (a) whole-brain vertex-wise structural magnetic resonance imaging (MRI) to measure cortical thickness, (b) resting-state functional connectivity MRI (rs-fcMRI) to measure global brain connectivity (GBC), and (c) diffusion MRI to measure diffusion GBC (dGBC), a measure of microstructural architecture and connectivity. Veterans will be matched on age, sex, PTSD symptom severity, and history of traumatic brain injury. This study may identify biomarkers of treatment targets in two of the operational priority areas for the VA ? suicide and PTSD, inform novel drug development of efficacious pharmacologic interventions, and ultimately advance the field making way to alleviate suffering of millions of individuals ? Veteran and civilian alike - struggling with suicidality. Candidate: Dr. Averill has demonstrated an unwavering commitment to improving Veterans? mental health care, with emphasis on PTSD and suicide prevention for well over a decade. Short-term goals include receipt of the CDA-2 to both advance her expertise through rigorous training objectives (focused on the neurobiology of SI/SA, multimodal neuroimaging, and statistics) and to provide data for future funding as she establishes a niche program of research in the National Center for PTSD-Clinical Neurosciences Division (NCPTSD-CND). Long-term goals include becoming a thought leader in the areas of suicide prevention and PTSD in Veterans through empirical investigations aimed at informing novel drug development and improved prevention, diagnostics, identification of biomarkers of risk and resilience in SI/SA, and treatment options. Environment: The infrastructure, quality of mentors, supplementary funding support, technology, and Veteran-focused research environment available at the National Center for PTSD-Clinical Neurosciences Division and Yale are unparalleled. This offers unique opportunity to support Dr. Averill in her transition to independence though exceptional targeted training/mentorship and to conduct a low cost/high yield study with great potential to advance the field, lead to improved outcomes for Veterans, and set a foundation for a successful VA-centric career.